TALES OF TWO SIMILAR
HYPOTHESES:
THE RISE AND FALL OF CHEMICAL
AND RADIATION HORMESIS

Edward J. Calabrese1 and Linda A. Baldwin

Department of Environmental Health Sciences

School of Public Health

N344 Morrill Science Center

University of Massachusetts

Amherst, MA 01003

Tel: 413-545-3164

Fax: 413-545-4692

Email: edwardc@schoolph.umass.edu

1 To whom correspondence should be sent

ABSTRACT

This paper compares the historical developments of chemical and radiation hormesis from their
respective inceptions in the late 1880's for chemical hormesis and early 1900's for radiation hormesis to the mid 1930's to
1940 during which both hypotheses rose to some prominence but then became marginalized within the scientific
community. This analysis documents that there were marked differences in their respective temporal developments, and
the direction and maturity of research. In general, the formulation of the chemical hormesis hypothesis displayed
an earlier, more-extensive and more sophisticated development than the radiation hormesis hypothesis. It was able
to attract prestigious researchers with international reputations from leading institutions, to be the subject of
numerous dissertations, to have its findings published in leading journals, and to have its concepts incorporated into
leading microbiological texts. While both areas became the object of criticism from leading scientists, the intensity of
the challenge was greatest for chemical hormesis due to its more visible association with the medical practice of
homeopathy. Despite the presence of legitimate and flawed criticism, the most significant limitations of both chemical
and radiation hormesis and their respective ultimate undoing were due to their: (1) lack of development of a
coherent dose-response theory using data of low dose stimulation from both the chemical and radiation domains; (2)
difficulty in replication of low dose stimulatory responses without an adequate study design especially with respect to an
appropriate number and properly spaced doses below the toxic threshold; (3) modest degree of stimulation even
under optimal conditions which was difficult to distinguish from normal variation; and (4) lack of appreciation of
the practical and/or commercial applications of the concepts of low dose stimulation.

We have recently assessed the early history of
chemical1 and radiation2 hormesis and factors contributing to
their respective marginalization within the scientific
community.3,4 As a result of these assessments it became clear
that chemical and radiation hormesis displayed an historical development quite distinct from each other with respect
to temporal development, scientific maturity and sophistication, animal and plant models studied, type and motivation
of scientific opposition, and consideration for commercial application. It should be noted that the term hormesis
was proposed in 1943 by Southam and
Erhlich5 who observed that chemical extracts of cedar stimulated fungal growth
at low doses, but inhibited at higher doses. The authors were apparently unaware of the fact that this phenomenon
was previously characterized as either the Arndt-Schulz Law or Hueppe's Rule. This paper will use the term hormesis
to describe the low dose stimulatory phenomenon but is cognizant that this term was created after the early
historical development and scientific marginalization of both chemical and radiation low dose stimulation (e.g.,
Arndt-Schulz Law) hypotheses.

The present paper will extend these previous efforts by directly comparing both chemical and radiation
hormesis with respect to their scientific development and research directions, the quality of their developmental maturity,
and generalizability of their two hypotheses, as well as their respective underlying weaknesses which led to the demise
of each hypothesis.

CHEMICAL HORMESIS DEVELOPS EARLIER THAN RADIATION HORMESIS

The concept of low dose chemical stimulation had its origins in the later decades of the
19th century. The predominant direction in these early years concerned the effects of various chemical agents on plant and fungal
growth (Table 1). In fact, prior to 1900, the general belief had emerged in the realm of chemical toxicology that low doses
as a general rule had the capacity to stimulate, while higher doses would inhibit the activity. This so-called
truism became referred to as either the Arndt-Schulz Law or Hueppe's Rule as a result of Hugo Schulz's research on
chemical stimulation of yeast
metabolism51,90,91 and Ferdinand Hueppe's research on chemical stimulation of
bacterial growth.78

The concept of radiation hormesis followed that of chemical hormesis and of course had to await the discovery
of X-rays in 1895 by Roentgen, uranium by Becquerel in 1896 and radium by the Curies in 1898. However, the
biological effects of ultraviolet (UV) radiation was actively researched much earlier with the report of Downs and
Blount92 being credited with the discovery of the killing action of sunlight on bacteria and other microorganisms, thereby
drawing attention to the importance of chemically active spectral radiation. By the 1890's it was clear that UV light was
an important factor, if not the principal factor, in the reported lethal effects of sunlight. By the early years of the
20th century, the region of lethal actions had been considerably refined to progressively more specific UV
wavelengths93 (Table 2).

Thus, it was quite clear that evaluation of the concept of low dose chemical stimulation had a strong
headstart over its radiation counterpart. This differential advance in favor of chemical hormesis can be seen not only in
the sheer volume of published research activity, but also in what was studied (Figure 1). In general, the most active
early areas of low dose chemical stimulation research was that of plant growth, followed by fungal growth and
metabolism, with bacterial metabolism a distant third (Table 1, Figure 1). By the end of the
19th century, there had been considerable activity in these two dominant areas principally driven by hopes of industrial and/or agricultural applications.
In the case of plant research, there was the obvious interest in the enhancement of agricultural productivity, while in
the case of fungal growth and metabolism there was great interest in finding ways to enhance, refine, and apply
the process of fermentation.

In the case of plant growth a separate line of research developed in the late 1890's by Kahlenberg and his
associates at the University of
Wisconsin39-41 who were more concerned with the assessment of the biological effects of
highly dilute solutions based principally on the application of newly developed concepts of physical chemistry permitting
the use of molar solutions rather than percentages as had been the case

In the case of chemical stimulation of plant growth, the first decade of the
20th century witnessed the transformation of relatively naïve experimental designs into an impressive formulation of concepts that established a
strong foundation for low dose chemical research. Most notably during the first decade of the
20th century were the contributions of True and
Gies,42 Cameron and
Breazeale,43 True and
Oglevee,44 Jensen,45 and Schreiner and
Reed.34 These investigators incorporated the concept of large numbers of doses, doses below toxic thresholds, and high sample
sizes along with the concurrent measurement of multiple endpoints. In addition, these authors began to display these
data on highly illustrative graphs enhancing presentation of the data and conceptual understanding.

During the late 1890's initial hypotheses were formulated concerning the underlying mechanism of the low
dose response and the role of such mechanisms in the organism's metabolism. For example,
Townsend15 first proposed that low dose chemical stimulation was an overcompensation for chemically induced injury, an observation that
was subsequently supported and generalized to other models during these early years of
development.132,133 In fact, this initial concept of
Townsend15 remains the dominant conceptual explanation of the low dose stimulatory
phenomenon.134 In addition,
Richards55,56 proposed the concept of enhancement of metabolic economic efficiency as a
result of exposure to low levels of chemical stress. While these conceptual frameworks were being developed and
debated, True and Oglevee44 developed the first graphing of the so-called hormetic
-ß-curve with respect to dose stimulatory range, maximum stimulatory response, and relationship of the maximum stimulatory response to the toxic
threshold which were remarkably similar to more modern
representations.135,136 All of these developments occurred well
before the genuine onset of low dose stimulatory research in the radiation domain.

The course of low dose radiation research displayed both similar and different research tracts than that for
the chemical hormesis research. The most significant area of similarity was the interest in the effects of X-rays and
radium on plant growth. The quality of the study designs with respect to low dose radiation stimulation of plant growth
did not reflect the rapidly developing maturity of the chemical hormesis researchers. For example, by 1900 the area
of low dose chemical stimulation was well on its way to having adopted modern study design criteria, whereas the
early researchers in the area of radiation hormesis often displayed noticeable deficits in study design. This was
clearly illustrated in the publication of
Gager94 who often employed in his over 90 experiments inadequate sample
size, inadequate reporting of experimental methods and overinterpretation of preliminary findings. However, this
differential maturity seen in the design, conduct, and interpretation of early low dose stimulation studies appeared to
be related to the fact that the first wave of chemical researchers in the U.S., such as True, Jensen, and Stevens, were
part of the broader and well established plant/agricultural research community with considerable laboratory and
field research experience. In addition, there was a strong tendency to publish in the most well established journals of
that era, such as the Botanical Gazette, which further insured a more advanced professional product.

Part of the differential quality of the earlier investigations on radiation effects on plant growth was the
difficulty in establishing a quantifiable radiation dose metric. When this became established by the early 1920's it
encouraged researchers in the plant area to collaborate more effectively with persons trained in radiation dosimetry. For
example, the 1931 study by Failla and
Henshaw137 represents an excellent collaboration between radiation dosimetry
experise (Failla) and plant biology (Henshaw). However, this challenge of bringing together such initially divergent
expertise resulted in the differential rate of maturity between the chemical and radiation domains.

In addition to the above mentioned factors affecting the limitations in study design, it was also influenced by
both the object of exposure and technological developments. That is, the generally lower sample size among early
plant radiation researchers was influenced by the fact that exposure was usually administered to seeds rather than
the seedling or later developing plant and the fact that the X-ray Coolidge tube was of limited size and could only
accommodate a fixed number of seeds.138 This also affected studies with larger seeds more differentially. While it would
have appeared that such a technological limitation should not have been an issue, it nonetheless affected the sample
size of numerous earlier plant studies. The area of chemical plant research did not have such constraints.

Of particular note is that the first American researchers assessing potential low dose stimulatory effects of
X-rays on plant growth were at the University of Chicago in the late
1920's, 139,140 some 30 years after the discovery of
X-rays! The reasons for this late application to plant growth of low doses of X-rays in the U.S. are unknown, given its
widespread use in the plant domain in other countries including various European countries and Japan and the
earlier assessment and claims of radium induced plant growth stimulation in the
U.S.2

Perhaps the most aggressive area of research in low dose radiation was in the area of medical applications for
the treatment of various diseases. While X-rays were being used to treat tumors within a year of their discovery, it
took about ten years for the concept to emerge that certain "low" doses of X-rays (i.e., about 10-50% of the
human erythema dose, 60-300 R) to treat a wide spectrum of human inflammatory
diseases.141-145 This concept of
employing radiation at relatively low doses for therapeutic purposes never developed in an analogous fashion in the area
of chemical stimulation except in so far as the Arndt-Schulz Law became a theoretical framework to support the
medical practice of homeopathy. However, in the case of radiation the low dose X-ray treatment was part of the
traditional medical establishment with publications and advances in this area in such journals as the Journal of the
American Medical Association, the New England Journal of Medicine, Radiology, and others. Thus, in contrast to the
relationship of chemical hormesis to the fringe medical practice of homeopathy low dose radiation therapy was part of
the traditional medical establishment.

Other notable developments included the later and active research of UV on fungi in the 1920's and
1930's.
(Table 2). In fact, it was during this research that the
first conceptual development of hormetic mechanisms
was presented by radiation hormesis researchers. That
is, Smith125 reported that UV-induced mycelium
growth occurred only after an initial injury. This concept
was quite similar to that reported almost 40 years before
by Townsend.15

SIMILARITIES AND DIFFERENCES IN THE OBJECTS OF STUDY
IN CHEMICAL AND RADIATION HORMESIS

A marked difference between the chemical and radiation low dose stimulatory response was the
near total absence of such observations with radiation
on bacteria, but the striking productivity of this area in
the chemical domain in the 1920's and 1930's (Tables 1
and 2) particularly at Yale University where a long series
of Ph.D. students under the highly respected
Professor Winslow clearly established the reproducible nature
of the hormetic response. Of particular note was
the research of Hotchkiss89 who assessed the effects of
twenty-three chemical agents on bacterial growth, with
fifteen demonstrating low dose stimulatory effects. The work
of Hotchkiss89 was remarkable for its strong study
design features, large number of doses especially below
the toxic threshold, and consistent nature of the low
dose stimulatory response. In fact, these and the
related findings of Winslow's other students became
incorporated into leading microbiological texts of the mid
20th century146-148 along with incorporation of standard
assays in laboratory exercises for introductory college
students.149

A general area that was pursued by those involved
in radiation but not chemical hormetic research was
the area of cell division. This is seen in research
concerning cell division in paramecia, the chick embryo, and
various cell types. This research became more substantial in
the 1920's with the generally consistent conclusion that
low doses of X-rays can stimulate cell division in a variety
of models.

The role of low dose stimulatory responses
generally did not address the issue of longevity during the
early years of the 20th century. However, two excellent
papers were provided by Davey of General Electric in which
he unexpectedly reported a low dose of X-rays
enhanced longevity in the confused flour
beetle.128 These findings were confirmed and extended in a follow-up paper
by the same author.129 No comparable paper was
presented on the chemical side. However, even more surprising
is that the striking findings of
Davey128,129 were not followed up for some forty years until
Cork150 confirmed the life extending response with a gamma ray source using
the same animal model.

In summary, the development of research in the
area of chemical hormesis occurred earlier, was more
extensive, and considerably more mature with respect to
the quality of study design and conceptual understanding
of a mechanistic framework. However, the two areas
are similar in that both were influenced in their
early development by commercial applications.

With respect to commercial applications the
most visible and high stakes activities were
concentrated within the area of radiation hormesis. In these cases
a number of attempts explored the use of radionuclides
to enhance plant growth. By 1923 a patent was issued on
a process to cause radiation induced stimulation of
plant growth.151 A number of commercial businesses
were created for this purpose but with little tangible and
no long lasting success.96,152 Factors affecting the lack
of apparent commercial success were complex,
involving technological, biological, social, and economic
factors. From the biological perspective, the "fact" of
stimulation was assumed to have been proven before
reasonably convincing data had been established. In addition,
there was little appreciation at that time (i.e.,
1915-1930) concerning the nature of low dose stimulation
dose-response relationship, including the recognition that
the average maximum increase would only be 30-60%
above controls and that each plant species and perhaps
each set of experimental conditions could display a
different optimal dose. Such complexity especially in a
new developing area clearly provided the basis for failure
for commercial success. In addition, the cost of radium
for potential use as fertilizer was quite high, being
about $100,000/gram in 1915.99 In order to double the
background levels of radium emanation (radon) in the
soil, Ramsey100 estimated one must use 75
milligrams/acre (i.e., $7500/acre).

The area of low dose clinical treatment with
X-rays had a long term series of successes that were
adequately documented in highly prestigious
journals.141-145 However, X-ray treatment, like other treatments, competed as
a therapeutic option with other available treatments
and/or procedures. In the case of X-ray treatment of
inflammatory diseases, it eventually lost out to advances
in chemotherapeutics which was reinforced with a
growing concern over potentially harmful effects of X-rays even
at low doses.

WHY RADIATION AND CHEMICAL HORMESIS WERE REJECTED

The rejecting of chemical and radiation
hormesis hypotheses has some general overlapping features but
a number of distinctive aspects as well. First, while
this discussion has divided the debate into chemical
and radiation hormesis, it is not clear that either one of
these areas were identified as a stand alone "field". In the
case of chemical hormesis it was uncommon for plant
chemical hormesis researchers to cite those in other
chemical areas such as fungi and bacteria. Furthermore,
the chemical and radiation hormesis researchers
generally never cited each other. In addition, there was a dearth
of review papers on the topic of low dose
stimulatory responses. This lead to only a very limited
summarization of relevant papers in either the introduction or
discussion of focused research reports. While this
intellectual truncation is appropriate for narrow research papers,
the general lack of critical broad reviews of the
literature limited the capacity to develop more integrated
assessments of the broad scientific literature. While
the publication of critical and integrated reviews is
common today, in the early decades of the
20th century it was not common. In fact, it is ironic that the first major review
of the literature on radiation hormesis was of a
highly critical nature (Johnson153 ­ see below). This lack
of broad integration coupled with the absence of a
central dose-response concept resulted in a poorly
developed general understanding of hormetic
dose-response relationships. Thus, low dose stimulatory findings
were quite truncated into very narrow model (e.g.,
plant, bacteria, etc.) specific responses with little attempt
to develop a general focus on dose-response
relationships. Such a lack of an integrated focus on the hormetic
dose-response was a fundamental underlying factor
that contributed to the inability of these hypotheses to
better establish themselves.

Radiation hormesis, with a more limited database
to support its premise than chemical hormesis, became
the object of a highly successful attack by Edna Johnson
in the 1930's.153,154 Of particular significance was that
the Johnson criticism targeted the strongest
experimental basis of radiation hormesis, that is, the effects of
X-rays on plant growth. As noted above, the review of
Johnson153 was not only one of the first major reviews of the
literature on the effects of X-rays on plant growth it
also received additional prestige for being part of a
major National Research Council (NRC) assessment of
the biological effects of radiation. This combination
proved to have considerably greater impact than
criticism tucked away in a discussion section of a focused
research paper. With the X-ray/plant component of the
radiation hormesis perspective placed on weakened grounds
by the review of Johnson,153 there was little
countervailing opposition to offset the criticism or limit its
impact. More specifically, there was no corresponding
supportive evidence with bacteria, and only limited
supportive evidence with fungi (Table 2). The only other
potential widespread strength supporting the concept of low
dose stimulation was in the area of medical treatment and
this itself was on weak grounds due to overzealous claims
for beneficial radiation exposure (e.g., mild
radium therapy)155 and growing fears of low dose mutational
and cancerous effects of X-rays.156

The demise of radiation hormesis is
understandable especially in light of its limited database, difficult
findings to reproduce, harsh criticism from leading
scientists coupled with a growing fear of radiation and an
emphasis on defining safety standards that required
defining frankly toxic effect levels, lowest adverse effect levels
and toxic thresholds. These became the predominant questions in the mid 1930's, not whether low doses
cause a marginal, hard to reproduce and even harder
to interpret stimulatory response. Once radiation
hormesis was pushed aside and not considered credible,
funding became generally unavailable and it became
further marginalized.

The chemical hormesis area should have survived
as a central hypothesis not only as a result of its
better general database but also because it had direct
linkage with numerous well known scientists or their
students such as Louis Pasteur [Raulin's
work50 in Pasteur's laboratory], Robert Koch [Ferdinand
Hueppe78 was a protégé of Koch], Wilhelm Ostwald [Kahlenberg
(see Kahlenberg and True; 39 Copeland and
Kahlenberg41) received his Ph.D. with Ostwald in Germany
before returning to the University of Wisconsin],
Charles Richet157,158 (the Nobel laureate for discovering
anaphylaxis) who demonstrated low dose stimulatory effects
in fermentation systems, and a strong series of U.S.
academics at prestigious institutions (i.e., Duggar at the
University of Wisconsin, Townsend and Richards at
Columbia University, Stevens at the University of Chicago and
later at Stanford University, Winslow at Yale University)
and True with the U.S. Agricultural Research Service
after moving from the University of Wisconsin. No
comparable grouping of outstanding researchers with
such powerful lineages and/or institutions and strong
publication records were present with radiation hormesis.
Yet despite the greater historical foundations, stronger
data, acceptance as a central concept in bacteriology and
long listings of prestigious scientists supporting it, all
factors less developed in radiation hormesis, both chemical
and radiation met the same fate of marginalization about
the same time.

Despite the above outstanding research and academic pedigree of hormesis researchers of the
early decades of the 20th century, the area of low dose
chemical stimulation was to become the object of
intense criticism by the next generation of dominant figures
in the field of pharmacology and toxicology. This
criticism was to have its origin in the fact that this area of
research was too closely allied with the controversial
medical practice of homeopathy.1 The area of chemical
hormesis had become used as an explanatory factor by
advocates of the medical practice of homeopathy. In fact,
Hugo Schulz, the microbiologist who first reported that
low doses of numerous chemicals stimulated yeast
metabolism, joined with Rudolph Arndt (the
homeopathic physician) and together promoted the
broad generalizability of the low dose stimulatory curve into
a prime explanatory framework of how homeopathic drugs worked. This close association of a
scientific hypothesis with a politicized medical practice
was criticized as early as 1896 by
Hueppe.78 Nonetheless, the association of hormesis to homeopathy remains even
to the present.159 However, in 1937 the prestigious
pharmacologist A.J. Clark of the University of
Edinborough published his classic text, "Handbook of
Pharmacology", in which he devoted 15% to a refutation of the
Arndt-Schulz Law.160 Clark, the discoverer of the first
molecular receptor (i.e., the acetylcholine receptor), was a
towering scientific feature by himself, but he also had an
unusually strong collaboration with several of the most
powerful and respected biostatisticians of that era.

At this time, the fundamental nature of the
dose-response was powerfully articulated and was
greatly affected by the very biostatisticians (e.g., Bliss,
Trevan) who worked with Clark. Lacking any
comparable countervailing intellectual force at the time, the
concept of hormesis, especially chemical hormesis, became
a cultural victim of guilt by association with
homeopathy. This marginalization was encouraged by
traditional medical philosophy because of the long standing
antipathy with homeopathy. Since pharmacology and
toxicology developed most extensively within
traditional medical schools, it was only natural to have
physician-trained pharmacologists/toxicologists lump
hormesis with homeopathy and the marginalization was complete.

DISCUSSION

This paper has argued that the concepts of
chemical and radiation hormesis had remarkably
independent histories with respect to temporal development,
direction of research, selection of experimental
model, quantity and quality of supportive data, acceptance
by the broader scientific community and commercial applications. While it may be the case that the
entire fields of chemical and radiation hormesis are
perceived as simply one concept, the actual unfolding of these
two areas of research has been quite distinct. The
separate developments of chemical and radiation hormesis
which are seen at the start of the 20th century has been
maintained to the present time. Thus, even today there is
very little cross communication between those working in
the areas of radiation and chemical hormesis.

Even in their respective demises there was also considerable uniqueness (Table 3). That is, the area
of chemical hormesis was plagued by its long standing
and close association with the medical practice of
homeopathy which set the stage for a guilt by association
response from traditional medicine which was strongly
influencing textbook development, professional society activities
and funding programs. In contrast, radiation hormesis
was plagued by the high dose applications of radiation
which dominated medical practices and made many ill, and
the overzealous claims of radium profiteers with the
highly visible and tragic death of the millionaire
industrialist and playboy Eben M. Byers, which resulted in the end
of the era of mild radium therapy.155

Table 3: Comparison of factors leading to the demise of chemical and radiation hormesis.

Both areas of hormesis were also plagued by
different but highly visible critics. In the case of
chemical hormesis the attack was profoundly more
intense, intentional, and systematic. As noted above, the
allocation of 15% of what has been referred to as a major
and classic text for the repudiation of the Arndt-Schulz
Law by A.J. Clark was the type of challenge that
radiation hormesis did not experience. Radiation
hormesis certainly had its critics, such as
Johnson,153 but they were more generally limited and focused within the
narrower context of a particular research paper. The use of
low dose radiation to treat human inflammatory
diseases became widely integrated within modern
medical practice from the early 1900's through the 1940's.
While these practices were not generally referred to as
being related to the Arndt-Schulz Law, there is little
question that its advocates such as Desjardin, chief of radiology
at the Mayo Clinic, clearly articulated the view that
low doses were beneficial for the patients' conditions
while higher doses were progressively less effective and
even higher doses harmful. The low dose X-ray therapy
which typically utilized only a single exposure was simply
out-competed by novel therapies of the mid 1940's such
as the progression of antibiotics which brought rapid
cures without the residual fears of adverse effects of
radiation treatment.

Despite dissimilarities in both chemical and
radiation hormesis, the most serious challenges were
ones they held in common (Table 3). That is the basic
reality that hormesis affected a modest stimulatory
response over a limited range of doses. It also requires
very stringent study design criteria and endpoint selection
in order to properly assess it. These factors affected both
its reproducibility and its commercial applications and
in the end these most fundamental factors are the
principal determining factors for their common demise.

ACKNOWLEDGMENT

This work was sponsored in part by a grant to
the University of Massachusetts (Edward J.
Calabrese, Prinicple Investigator) by the U.S. Nuclear
Regulatory Commission.

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